Bottom Line:
However, the molecular determinants of this restriction mechanism are unknown.Electrostatic potential on the protein-binding site is one of the properties regulating protein-protein interactions.Although HIV-2 GH123 and SIVmac239 capsid proteins share more than 87% amino acid identity, we observed a large difference between the two molecules with the HIV-2 GH123 molecule having predominantly positive and SIVmac239 predominantly negative electrostatic potential on the surface of the loop between α-helices 4 and 5 (L4/5).

ABSTRACTHuman immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus isolated from a macaque monkey (SIVmac) are assumed to have originated from simian immunodeficiency virus isolated from sooty mangabey (SIVsm). Despite their close similarity in genome structure, HIV-2 and SIVmac show different sensitivities to TRIM5α, a host restriction factor against retroviruses. The replication of HIV-2 strains is potently restricted by rhesus (Rh) monkey TRIM5α, while that of SIVmac strain 239 (SIVmac239) is not. Viral capsid protein is the determinant of this differential sensitivity to TRIM5α, as the HIV-2 mutant carrying SIVmac239 capsid protein evaded Rh TRIM5α-mediated restriction. However, the molecular determinants of this restriction mechanism are unknown. Electrostatic potential on the protein-binding site is one of the properties regulating protein-protein interactions. In this study, we investigated the electrostatic potential on the interaction surface of capsid protein of HIV-2 strain GH123 and SIVmac239. Although HIV-2 GH123 and SIVmac239 capsid proteins share more than 87% amino acid identity, we observed a large difference between the two molecules with the HIV-2 GH123 molecule having predominantly positive and SIVmac239 predominantly negative electrostatic potential on the surface of the loop between α-helices 4 and 5 (L4/5). As L4/5 is one of the major determinants of Rh TRIM5α sensitivity of these viruses, the present results suggest that the binding site of the Rh TRIM5α may show complementarity to the HIV-2 GH123 capsid surface charge distribution.

Figure 1: (A)Sensitivities of HIV-2 GH123, HIV-2 GH123 mutant carrying SIVmac239 capsid protein (HIV-2 GH/SCA), and SIVmac239 to cynomolgus (CM) and rhesus (Rh) monkey TRIM5α. The replication of HIV-2 GH123 was potently restricted by CM and Rh TRIM5α (sensitive), while that of SIVmac239 and the HIV-2 GH123 mutant carrying SIVmac239 capsid was not (resistant). (B) Alignment of amino acid sequences of HIV-2 GH123 and SIVmac239 capsid proteins. Positions of the N-terminal loop (N-terminal), a loop between α-helices 4 and 5 (L4/5), and a loop between α-helices 6 and 7 (L6/7) are indicated above the amino acid sequences.

Mentions:
Previously, we evaluated the sensitivity of HIV-2 GH123 and SIVmac239 to Rh and CM TRIM5αs, and found that HIV-2 GH123 was sensitive to CM and Rh TRIM5αs (Song et al., 2007; Kono et al., 2008; Figure 1A). In contrast, SIVmac239 was resistant to CM and Rh TRIM5αs (Kono et al., 2008, 2010; Figure 1A). CA is the determinant for this differential sensitivity to TRIM5α between HIV-2 GH123 and SIVmac239, as the HIV-2 GH123 mutant carrying SIVmac239 CA (HIV-2 GH/SCA) was also resistant to CM and Rh TRIM5αs (Figure 1A; Kono et al., 2010). Despite this marked difference in TRIM5α sensitivity between HIV-2 GH123 and SIVmac239, CA of these two viruses share more than 87% amino acid identity (Figure 1B). Therefore, we compared the structural properties of HIV-2 GH123 CA with those of SIVmac239.

Figure 1: (A)Sensitivities of HIV-2 GH123, HIV-2 GH123 mutant carrying SIVmac239 capsid protein (HIV-2 GH/SCA), and SIVmac239 to cynomolgus (CM) and rhesus (Rh) monkey TRIM5α. The replication of HIV-2 GH123 was potently restricted by CM and Rh TRIM5α (sensitive), while that of SIVmac239 and the HIV-2 GH123 mutant carrying SIVmac239 capsid was not (resistant). (B) Alignment of amino acid sequences of HIV-2 GH123 and SIVmac239 capsid proteins. Positions of the N-terminal loop (N-terminal), a loop between α-helices 4 and 5 (L4/5), and a loop between α-helices 6 and 7 (L6/7) are indicated above the amino acid sequences.

Mentions:
Previously, we evaluated the sensitivity of HIV-2 GH123 and SIVmac239 to Rh and CM TRIM5αs, and found that HIV-2 GH123 was sensitive to CM and Rh TRIM5αs (Song et al., 2007; Kono et al., 2008; Figure 1A). In contrast, SIVmac239 was resistant to CM and Rh TRIM5αs (Kono et al., 2008, 2010; Figure 1A). CA is the determinant for this differential sensitivity to TRIM5α between HIV-2 GH123 and SIVmac239, as the HIV-2 GH123 mutant carrying SIVmac239 CA (HIV-2 GH/SCA) was also resistant to CM and Rh TRIM5αs (Figure 1A; Kono et al., 2010). Despite this marked difference in TRIM5α sensitivity between HIV-2 GH123 and SIVmac239, CA of these two viruses share more than 87% amino acid identity (Figure 1B). Therefore, we compared the structural properties of HIV-2 GH123 CA with those of SIVmac239.

Bottom Line:
However, the molecular determinants of this restriction mechanism are unknown.Electrostatic potential on the protein-binding site is one of the properties regulating protein-protein interactions.Although HIV-2 GH123 and SIVmac239 capsid proteins share more than 87% amino acid identity, we observed a large difference between the two molecules with the HIV-2 GH123 molecule having predominantly positive and SIVmac239 predominantly negative electrostatic potential on the surface of the loop between α-helices 4 and 5 (L4/5).

ABSTRACTHuman immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus isolated from a macaque monkey (SIVmac) are assumed to have originated from simian immunodeficiency virus isolated from sooty mangabey (SIVsm). Despite their close similarity in genome structure, HIV-2 and SIVmac show different sensitivities to TRIM5α, a host restriction factor against retroviruses. The replication of HIV-2 strains is potently restricted by rhesus (Rh) monkey TRIM5α, while that of SIVmac strain 239 (SIVmac239) is not. Viral capsid protein is the determinant of this differential sensitivity to TRIM5α, as the HIV-2 mutant carrying SIVmac239 capsid protein evaded Rh TRIM5α-mediated restriction. However, the molecular determinants of this restriction mechanism are unknown. Electrostatic potential on the protein-binding site is one of the properties regulating protein-protein interactions. In this study, we investigated the electrostatic potential on the interaction surface of capsid protein of HIV-2 strain GH123 and SIVmac239. Although HIV-2 GH123 and SIVmac239 capsid proteins share more than 87% amino acid identity, we observed a large difference between the two molecules with the HIV-2 GH123 molecule having predominantly positive and SIVmac239 predominantly negative electrostatic potential on the surface of the loop between α-helices 4 and 5 (L4/5). As L4/5 is one of the major determinants of Rh TRIM5α sensitivity of these viruses, the present results suggest that the binding site of the Rh TRIM5α may show complementarity to the HIV-2 GH123 capsid surface charge distribution.